Psychotic disorders, especially schizophrenia, are severe mental disorders which extremely impair daily life. The symptoms of psychosis may be divided into two fractions. In the acute phase, it is predominated by hallucinations and delusions being called the positive symptoms. When the agitated phase abates the so called negative symptoms become obvious. They include cognitive deficits, social phobia, reduced vigilance, indifference and deficits in verbal learning and memory, verbal fluency and motor function.
Although several antipsychotics are available since, the present therapy of psychosis is not satisfactory. The classic antipsychotics, such as haloperidol, with a high affinity to dopamine D2 receptor show extreme side effects, such extrapyramidal symptoms (=EPS) and do not improve the negative symptoms of schizophrenia so that they do not enable the patient to return to everyday life.
Clozapine which has emerged as a benchmark therapeutic ameliorating positive, negative and cognitive symptoms of schizophrenia and devoid of EPS shows agranulocytosis as a major, potential lethal side-effect (Capuano et al., 2002). Besides, there is still a high amount of therapy resistant cases (Lindenmayer et al., 2002).
In conclusion, there is still a need for developing new antipsychotics which ameliorate positive, negative and cognitive symptoms of psychosis and have a better side effect profile.
The exact pathomechanism of psychosis is not yet known. A dysfunction of several nreurotransmitter systems has been shown. The two major neurotransmitter systems that are involved are the dopaminergic and the glutamatergic system:
Thus, acute psychotic symptoms may be stimulated by dopaminergic drugs (Capuano et al., 2002) and classical antipsychotics, like haloperidol, have a high affinity to the dopamine D2 receptor (Nyberg et al., 2002). Animal models based on a hyperactivity of the dopaminergic neurotransmitter system (amphetamine hyperactivity, apomorphine climbing) are used to mimic the positive symptoms of schizophrenia.
Additional there is growing evidence that the glutamatergic neurotransmitter system plays an important role in the development of schizophrenia (Millan, 2005). Thus, NMDA antagonists like phencyclidine and ketamine are able to stimulate schizophrenic symptoms in humans and rodents (Abi-Saab et al., 1998; Lahti et al., 2001). Acute administration of phencyclidine and MK-801 induce hyperactivity, stereotypies and ataxia in rats mimicking psychotic symptoms. Moreover, in contrast to the dopaminergic models the animal models of psychosis based on NMDA antagonists do not only mimic the positive symptoms but also the negative and cognitive symptoms of psychosis (Abi-Saab et al., 1998; Jentsch and Roth, 1999). Thus, NMDA antagonists, additionally induce cognitive deficits and social interaction deficits.
Eleven families of phosphodiesterases have been identified in mammals so far (Essayan, 2001). The role of PDEs in the cell signal cascade is to inactivate the cyclic nucleotides cAMP and/or cGMP (Soderling and Beavo, 2000). Since cAMP and cGMP are important second messenger in the signal cascade of G-protein-coupled receptors PDEs are involved in a broad range of physiological mechanisms playing a role in the homeostasis of the organism.
The PDE families differ in their substrate specificity for the cyclic nucleotides, their mechanism of regulation and their sensitivity to inhibitors. Moreover, they are differentially localized in the organism, among the cells of an organ and even within the cells. These differences lead to a differentiated involvement of the PDE families in the various physiological functions.
PDE10A is primarily expressed in the brain and here in the nucleus accumbens and the caudate putamen. Areas with moderate expression are the thalamus, hippocampus, frontal cortex and olfactory tubercle (Menniti et al., 2001). All these brain areas are described to participate in the pathomechanism of schizophrenia (Lapiz et al. 2003) so that the location of the enzyme indicates a predominate role in the pathomechanism of psychosis.
In the striatum PDE10A is predominately found in the medium spiny neurons and there are primarily associated to the postsynaptic membranes of these neurons (Xie et al., 2006). By this location PDE10A may have an important influence on the signal cascade induced by dopaminergic and glutamatergic input on the medium spiny neurons two neurotransmitter systems playing a predominate role in the pathomechanism of psychosis.
Phosphodiesterase (PDE) OA, in particular, hydrolyses both cAMP and cGMP having a higher affinity for cAMP (Km=0.05 μM) than for cGMP (KM=3 μM) (Sonderling et al., 1999).
Psychotic patients have been shown to have a dysfunction of cGMP and cAMP levels and its downstream substrates (Kaiya, 1992; Muly, 2002; Garver et al., 1982). Additionally, haloperidol treatment has been associated with increased cAMP and cGMP levels in rats and patients, respectively (Leveque et al., 2000; Gattaz et al., 1984). As PDE10 hydrolyses both cAMP and cGMP (Kotera et al., 1999) an inhibition of PDE10A would also induce an increase of cAMP and cGMP and thereby having a similar effect on cyclic nucleotide levels as haloperidol.
The antipsychotic potential of PDE10A inhibitors is further supported by studies of Kostowski et al. (1976) who showed that papaverine, a moderate selective PDE10A inhibitor, reduces apomorphine-induced stereotypies in rats, an animal model of psychosis, and increases haloperidol-induced catalepsy in rats while concurrently reducing dopamine concentration in rat brain. Activities that are also seen with classical antipsychotics. This is further supported by a patent application establishing papaverine as a PDE10A inhibitor for the treatment of psychosis (US Patent Application No. 2003/0032579).
In addition to classical antipsychotics which mainly ameliorate the positive symptoms of psychosis PDE10A also bears the potential to improve the negative and cognitive symptoms of psychosis.
Focusing on the dopaminergic input on the medium spiny neurons PDE10A inhibitors by up-regulating cAMP and cGMP levels act as D1 agonists and D2 antagonists because the activation of Gs-protein coupled dopamine D1 receptor increases intracellular cAMP, whereas the activation of the Gi-protein coupled dopamine D2 receptor decreases intracellular cAMP levels through inhibition of adenylyl cyclase activity (Mutschler et al., 2001).
Elevated intracellular cAMP levels mediated by D1 receptor signalling seems to modulate a series of neuronal processes responsible for working memory in the prefrontal cortex (Sawaguchi, 2000), and it is reported that D1 receptor activation may improve working memory deficits in schizophrenic patients (Castner et al., 2000). Thus, it seems likely that a further enhancement of this pathway might also improve the cognitive symptoms of schizophrenia.
Further indication of an effect of PDE10A inhibition on negative symptoms of psychosis are given by Rodefer et al. (2005) who could show that papaverine reverses attentional set-shifting deficits induced by subchronic administration of phencyclidine, an NMDA antagonist, in rats. Attentional deficits including an impairment of shifting attention to novel stimuli belongs to the negative symptoms of schizophrenia. In the study the attentional deficits were induced by administering phencyclidine for 7 days followed by a washout period. The PDE10A inhibitor papaverine was able to reverse the enduring deficits induced by the subchronic treatment.
Imidazo[1,5-a]pyrido[3,2-e]pyrazinones its synthesis and some medical uses are well described in patents and the literature.
The applications EP 0 400 583 and U.S. Pat. No. 5,055,465 from Berlex Laboratories, Inc. disclose a group of imidazoquinoxalinones, their aza analogs and a process for their preparation. These compounds have been found to have inodilatory, vasodilatory and venodilatory effects. The therapeutic activity is based on the inhibition of phosphodiesterase 3 (PDE3).
EP 0 736 532 discloses pyrido[3,2-e]pyrazinones and a process for their preparation. These compounds are described to have anti-asthmatic and anti-allergic properties. Examples of this invention are inhibitors of PDE4 and PDE5.
WO 00/43392 discloses the use of imidazo[1,5-a]pyrido[3,2-e]pyrazinones which are inhibitors of PDE3 and PDE5 for the therapy of erectile dysfunction, heart failure, pulmonic hypertonia and vascular diseases which are accompanied by insufficient blood supply.
An other group of pyrido[3,2-e]pyrazinones, disclosed in WO 01/68097 are inhibitors of PDE5 and can be used for the treatment of erectile dysfunction.
Further methods for the preparation of imidazo[1,5-a]pyrido[3,2-e]pyrazinones are described also by D. Norris et al. (Tetrahedron Letters 42 (2001), 4297-4299).
WO 92/22552 refers to imidazo[1,5-a]quinoxalines which are generally substituted at position 3 with a carboxylic acid group and derivatives thereof. These compounds are described to be useful as anxiolytic and sedative/hypnotic agents.
In contrast only a limited number of imidazo[1,5-a]pyrido[3,2-e]pyrazines and their medical use are already published.
WO 99/45009 describes a group of imidazopyrazines of formula (I)

Part of the definition of Q is to form a 6-membered heterocyclic ring including pyridin. While R1, R2 and R3 are representing a large variety of substituents the definition of the group —NR4R5 is of special importance.
R4 and R5 are each independently hydrogen, R6 or —C(O)R6 or the whole group NR4R5 forms a 3- to 8-membered saturated or unsaturated ring.
R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo or heterocycloalkyl, each of which is unsubstituted or substituted.
These compounds are described to be inhibitors of protein tyrosine kinases used in the treatment of protein tyrosine kinase-associated disorders such as immunologic disorders.
Interestingly, for all examples listed in claim 9 the structure of the group NR4R5 is limited in a way that one of R4 and R5 is hydrogen and for the other one R6 is phenyl (unsubstituted or substituted).
This structural selection of the group NR4R5 is inline with published SAR data from the same company (P. Chen et al., Bioorg. Med. Chem. Lett. 12 (2002), 1361-1364 and P. Chen et al., Bioorg. Med. Chem. Lett. 12 (2002), 3153-3156).